Interstitial Collagenase Is Expressed by Keratinocytes That Are Actively Involved in Reepithelialization in Blistering Skin Diseases

Abstract

Migrating keratinocytes actively involved in reepithelialization in dermal wounds acquire a collagenolytic phenotype upon contact with the dermal matrix. To determine whether this phenotype is associated with repair in other forms of wounds, we assessed collagenase expression in 50 specimens representing a variety of blistering skin diseases, including subtypes of epidermolysis bullosa, porphyria cutanea tarda, bullous pemphigoid, pemphigus, transient acantholytic dermatosis, and suction blisters. Distinct from that seen in chronic ulcers or in normal healing by second intention, reepithelialization in these blistering conditions was not necessarily associated with a complete loss of basement membrane, as determined by immunostaining for type IV collagen. Collagenase mRNA was detected in the basal keratinocytes of several specimens of epidermolysis bullosa simplex (six of 10) and of pemphigus (three of seven), as well as in one quarter of transient acantholytic dermatosis samples in the presence of an intact basement membrane. In contrast, three of nine porphyria cutanea tarda, one third of epidermolysis bullosa acquisita, and one of 10 bullous pemphigoid samples had collagenase-positive basal keratinocytes with the basement membrane disrupted. The collagenase-positive lesions generally represented older blisters with evidence of epithelial regeneration. Collagenase was also expressed in suction blisters at 2 and 5 d after induction of the blister, but was shut off when the epidermis had healed. Other metalloproteinases were expressed occasionally, if at all. Our results suggest that keratinocyte migration is associated with collagenase expression and that contact of keratinocytes with the dermal matrix is not necessarily needed for collagenase induction.

Induction and Repression of Collagenase-1 by Keratinocytes Is Controlled by Distinct Components of Different Extracellular Matrix Compartments

“…One, as we (3,4) and others reported (6), immunostaining for type IV collagen or laminin showed that collagenase-1-positive keratinocytes are not in contact with a basement membrane but rather are moving over the dermal or wound bed matrix. Two, collagenase-1 is not expressed by basal keratinocytes in nonulcerative pyogenic granuloma or in blisters, such as bullous pemphigoid, which separate above basement membrane, but this MMP is expressed by migrating keratinocytes in blisters that form below the basement membrane, such as in recessive dystrophic epidermolysis bullosa (3,4). Three, in acute wounds (3,6) and in cultured skin equivalent models (20), collagenase-1 expression ceases once re-epithelialization is completed and a basement membrane has reformed.…”

“…Conversely, keratinocyte migration in and of itself does not induce collagenase-1 expression. For example, collagenase-1 is not expressed by keratinocytes involved in re-epithelialization of lesions with an intact basement membrane, such as suction blisters or early bullous pemphigoid blisters (3,4). In addition, collagenase-1 is not expressed by cultured keratinocytes on gelatin, even though these cells can migrate on this substrate (5).…”

“…Indeed, collagenase-1 is only expressed by keratinocytes that are not in contact with an intact basement membrane (3,4,6,7). Furthermore, expression of collagenase-1 is shut off once re-epithelialization is complete and the basement membrane is restored (3, 6).…”

“…In a thorough examination of normally healing wounds and of a variety of chronic ulcers, we found that collagenase-1, a member of the matrix metalloproteinase (MMP) 1 family with the ability to cleave fibrillar collagens type I, II, and III at a specific locus in their triple helical domain, is invariably expressed by basal keratinocytes at the edge of repairing tissue (2)(3)(4). In all, we have examined Ͼ100 different human skin specimens, representing a variety of chronic ulcers, blisters, and normally healing wounds, and in each sample with injury that breached the basement membrane, collagenase-1 was prominently and invariantly expressed by basal keratinocytes migrating over the dermal wound bed.…”

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

“…Skin healing is dependent upon several processes that comprise inflammation, protein synthesis, matrix deposition, migration and subsequent proliferation of keratinocytes (Kanzler et al, 1986;Clark, 1993). Keratinocytes are known to secrete numerous proteins that include proteolytic enzymes such as matrix metalloproteinases (Stamenkovic, 2003), interstitial collagenase (Saarialho-Kere et al, 1995) and cathepsin B (Buth et al, 2004). It is presumed that during the wound healing process, these proteolytic enzymes play a role in motility of keratinocytes by remodeling the extracellular matrix for migration of keratinocytes to peripheral layers of the epidermis.…”